Storage stable aqueous parenteral solutions comprising diclofenac

ABSTRACT

The present invention relates to stable, aqueous, parenteral solutions comprising diclofenac and polyvinylpyrrolidone, wherein the solutions are for parenteral (subcutaneous, intravenous and/or intramuscular) administration.

FIELD OF THE INVENTION

The present invention relates to stable, aqueous, parenteral solutions comprising diclofenac and polyvinylpyrrolidone, wherein the solutions are for parenteral (subcutaneous, intravenous and/or intramuscular) administration. The invention relates to method of treatment of migraine and/or pain and a kit containing pre-filled syringe of the parenteral solution. It also relates to processes for preparing such solutions.

BACKGROUND OF THE INVENTION

Diclofenac is widely prescribed analgesic and anti-inflammatory agent and may be administered via oral as well as parenteral route. Oral dose of diclofenac ranges from 100 mg to 200 mg per day, while parenteral dose ranges from 75 to 150 mg per day.

U.S. Pat. No. 5,389,681 discloses sterilizable parenteral solution comprising a diclofenac salt, solubilisers such as 1,2-propylene glycol or polyethylene glycol 300-400, stabilisers such as glutathione or N-acetyl cysteine and a carrier liquid, such as water.

Indian Application No. 1382/MUM/2008 discloses injectable composition comprising diclofenac, polyoxyl 35 castor oil, benzyl alcohol, sodium sulphite, disodium EDTA and water as a principal solvent.

U.S. Publication No. 2012/0142779 discloses parenteral aqueous solution comprising either (a) diclofenac or a pharmaceutically acceptable diclofenac salt and a cyclodextrin, or (b) an inclusion complex of diclofenac or a pharmaceutically acceptable diclofenac salt and a cyclodextrin, or a mixture of both.

Indian Application No. 1438/MUM/2012 discloses injectable composition comprising diclofenac and/or its acceptable salts, macrogol 15 hydroxystearate and pharmaceutically acceptable excipients.

Padiyar A. et al., International Journal of Advanced Pharmaceutics, 2016, 6 (2), 78-84, discloses a mixed solvency concept using solid solublizers for preparing injectable composition comprising diclofenac sodium in concentration 75 mg with a low volume of injection to 1 mL.

International Publication No. (PCT) WO 2016/170401 discloses injectable composition comprising diclofenac or water soluble salts thereof, in a solvent system containing water and two or more solubilizers, and optionally, one or more antioxidant (s) and/or one or more buffering agent (s) for administration via intradeltoid along with intragluteal, subcutaneous and slow intravenous route.

Migraine is a chronic neurovascular disorder characterized by recurrent attacks of often severe headache, typically accompanied by nausea/vomiting and sensitivity to light and/or sound. Pharmacologic approaches to the treatment of migraine include drugs to treat acute migraine attacks as they arise (acute treatment of migraine), and drugs to reduce the frequency of migraine attacks (preventive treatment).

CAMBIA® (Diclofenac Potassium for Oral Solution) is an oral formulation approved by the USFDA for the acute treatment of migraine attacks with or without aura in adults 18 years of age or older.

During acute migraine, gastrointestinal motility is reduced which results in impaired drug absorption. Also, nausea or vomiting accompanied with migraine, causes difficulty to the patient for oral medication. First pass metabolism of diclofenac potassium after oral administration of CAMBIA® has resulted in only approximately 50% bioavailability of the drug.

There still exists a need for a storage stable solution which enables safe and efficacious administration of concentrated solution of diclofenac either without pain or with minimal pain at the site of administration, and also suitable for administration via subcutaneous injection route to offer the advantages over existing oral dosage form, viz., providing quick onset of action, providing better/improved safety profile and/or providing better/improved patient convenience. A subcutaneous administration of a drug, as an alternate route, for the treatment of migraine can be a better option to avoid the above mentioned drawbacks.

SUMMARY OF THE INVENTION

In one general aspect, the present invention provides a stable, aqueous, parenteral solution comprising diclofenac and polyvinylpyrrolidone (PVP).

In another general aspect, the present invention provides a process for preparing the parenteral solution comprising diclofenac and polyvinylpyrrolidone.

In another general aspect, the present invention provides a method for the treatment of pain and inflammation, the method comprising administering to a human being in need thereof, a parenteral solution of the present invention either without pain or with minimal pain at the site of administration when administered via intravenous route or subcutaneous injection route.

In another general aspect, the present invention provides a kit comprising an autoinjector which contains a pre-filled syringe (a pre-filled syringe assembled/placed in an autoinjector), wherein the pre-filled syringe (PFS) is filled with a solution of a therapeutically effective amount of diclofenac sodium. The autoinjector provides convenience to the patient for self-administration.

In another general aspect, the present invention provides a method for the treatment of the acute treatment of migraine attacks with or without aura in adults (18 years of age or older), the method comprising administering a solution comprising diclofenac via subcutaneous route.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a stable, aqueous, parenteral solution comprising diclofenac and one or more pharmaceutically acceptable excipients.

The aqueous parenteral solution is in the form of a clear solution comprising diclofenac and polyvinylpyrrolidone.

The term “diclofenac” as used herein, unless and otherwise specifically mentioned, encompasses diclofenac base as well as its pharmaceutically acceptable salts, for example, diclofenac sodium and diclofenac potassium.

The storage stable aqueous parenteral solution may be administered via parenteral route, for example, intramuscular (intradeltoid, intragluteal etc.), subcutaneous, intravenous infusion or intravenous bolus route.

The term “about” as used herein, refers to encompass +/−20%, 15%, 10%, 5%, 2%, 1%, 0.5%, or 0.25% of the numerical value of the number with which it is being used.

The term “between” as used herein for the purpose of defining ranges, is inclusive of the lower and upper number of the range.

The term “storage stable” as used herein, refers to any composition comprising a drug having sufficient physical and chemical stability to allow storage at a convenient temperature, such as between about 0° C. and about 40° C., for a commercially reasonable period of time. The term “physical stability” refers to maintenance of color or colorless state, dissolved oxygen level, head space oxygen level, and particulate matter size. The term “chemical stability” relates to formation of drug-related impurities in terms of total impurities, known impurities and single maximum unknown impurity, up to allowed limits by the Regulatory Agency. For pharmaceutical products, stability is required for commercially relevant time after manufacturing, such as for about 1, 3, 6, 12, 18, 24 or 36 months, during which a product is kept in its original packaging under specified storage conditions. The term composition includes the solution prepared in accordance with the present invention.

The term “stable” as used herein, refers to any composition comprising a drug having sufficient physical and chemical stability at the time of manufacturing of the composition.

The term “controlled room temperature” as used herein, refers to the temperature between 20° C. and 25° C.

The term “T_(max)” as used herein, unless and otherwise specifically mentioned, means time to achieve maximum concentration of the drug in plasma, achieved after administration of the product (unit for example: minutes).

The term “C_(max)” as used herein, unless and otherwise specifically mentioned, means maximum concentration of drug in plasma, achieved after administration of the product (unit for example: ng/mL).

The term “AUC” as used herein, unless and otherwise specifically mentioned, means area under the curve for a plot of concentration of drug in plasma vs. time (unit for example: ng*h/mL).

In one embodiment, the present invention provides a stable parenteral solution comprising diclofenac, polyvinylpyrrolidone and water.

In another embodiment, the present invention provides a stable solution comprising diclofenac, polyvinylpyrrolidone, polysorbate 80, sodium chloride, one or more pH adjusting agents, and water for parenteral administration.

The stable aqueous parenteral solution may comprise diclofenac sodium in a concentration of between about 10 mg/mL and about 500 mg/mL, for example, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 37.5 mg/mL, about 40 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 250 mg/mL, about 275 mg/mL, about 300 mg/mL, about 325 mg/mL, about 350 mg/mL, about 375 mg/mL, about 400 mg/mL, about 425 mg/mL, about 450 mg/mL, about 475 mg/mL or about 500 mg/mL.

The stable aqueous parenteral solution may comprise polyvinylpyrrolidone in a concentration of between about 50 mg/mL and about 300 mg/mL, for example, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 100 mg/mL, about 120 mg/mL, about 140 mg/mL, about 160 mg/mL, about 180 mg/mL, about 200 mg/mL, about 220 mg/mL, about 250 mg/mL or about 280 mg/mL.

In another embodiment, the stable aqueous parenteral solution may comprise diclofenac in a concentration of 25 mg/mL, 37.5 mg/mL or 75 mg/mL, wherein upon dilution of the solution with appropriate amount of the D5NS (solution of 5 percent dextrose in saline (0.9% sodium chloride)) or saline solution (0.9% sodium chloride), it may provide a diluted solution for parenteral administration having diclofenac concentration of 0.75 mg/mL, 0.30 mg/mL or 0.15 mg/mL, which remains clear (free of any crystals/precipitates) after storage for 24 hours at controlled room temperature or at 2-8° C.

In one embodiment, the present invention provides a storage stable aqueous parenteral solution comprising diclofenac and one or more pharmaceutically acceptable excipients, wherein the solution retains at least 95% of the diclofenac.

In another embodiment, the present invention provides a storage stable aqueous parenteral solution comprising dicofenac, polyvinylpyrrolidone, polysorbate 80 and water, wherein the solution is storage stable after storage for 12 months at controlled room temperature.

The storage stable aqueous parenteral solution may retain at least 95% of the diclofenac sodium (% assay) after storage for at least 1 month, for example, 2 months, 3 months, 6 months, 12 months, 18 months or 24 months at controlled room temperature (CRT).

The storage stable aqueous parenteral solution may retain at least 95% of the diclofenac sodium (% assay) after storage for at least 1 month, for example, 2 months, 3 months, 6 months, 12 months, 18 months or 24 months at 25° C. temperature and 60% relative humidity (% RH).

The storage stable aqueous parenteral solution may retain at least 95% of the diclofenac sodium (% assay) after storage for at least 1 month, for example, 2 months, 3 months, 6 months, 12 months, 18 months or 24 months at 40° C. temperature and 75% RH.

In another embodiment, the stable aqueous parenteral solution comprising diclofenac is clear (free of any crystals/precipitates) by visual inspection after storage for at least 1 month, for example, 2 months, 3 months, 6 months, 12 months, 18 months or 24 months, at controlled room temperature. The solution may provide the value of absorbance not more than 1, for example, not more then 0.75, 0.5, 0.4, 0.3, 0.2, 0.1 or 0.05. The solution may provide the value of % transmittance not less than 90%, for example, not less than 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9%. The parenteral solution comprising diclofenac of the present invention does not form any precipitate and remains physically stable after storage for more than 2 months, for example, for 3 months, for 6 months, for 12 months, for 18 months, for 24 months or for 36 months when stored at 2° C.-8° C. temperature or at 25±2° C. temperature and 60±5% RH.

In another embodiment, the stable aqueous parenteral solution comprising diclofenac does not contain impurity A (1-(2,6-dichlorophenyl) indolin-2-one) more than 0.5%, for example, 0.4%, 0.3%, 0.2%, 0.1% or 0.05%, by weight of diclofenac, as measured by HPLC after storage for at least 1 month, for example, 2 months, 3 months, 6 months, 12 months, 18 months or 24 months, at controlled room temperature.

In another embodiment, the stable aqueous parenteral solution comprising diclofenac may have a viscosity value of between about 1.5 cP and 7.5 cP, for example, 2 cP, 2.5 cP, 3 cP, 3.5 cP, 4 cP, 4.5 cP, 5 cP, 5.5 cP, 6 cP, 6.5 cP or 7 cP.

In another embodiment, the stable aqueous parenteral solution comprising diclofenac may have an osmolality value of between about 200 mOsm and about 600 mOsm, for example, about 250 mOsm, about 300 mOsm, about 350 mOsm, about 400 mOsm, about 450 mOsm, about 500 mOsm or about 550 mOsm.

In another embodiment, the stable aqueous parenteral solution comprising diclofenac may have a pH of between about 7 and about 10, for example, about 7.5, about 8, about 8.5, about 9 or about 9.5.

The suitable pharmaceutically acceptable excipients for the solution of the present invention may include one or more pharmaceutically acceptable solvents, solubilizers, stabilizers, preservatives, antioxidants, surfactants, buffering agents, nucleation inhibitors, pH adjusting agents and isotonicity adjusting agents.

Examples of suitable pharmaceutically acceptable solvents may include, but not limited to, water for injection, and the like.

Examples of suitable pharmaceutically acceptable solubilizers may include, but not limited to benzyl benzoate, castor oil, cottonseed oil, N, N dimethylacetamide, dehydrated ethanol, glycerol, N-methyl-2-pyrrolidone, diethanolamine, L-arginine, peanut oil, poppyseed oil, safflower oil, sesame oil, soybean oil, vegetable oil, or any combination thereof.

Examples of suitable pharmaceutically acceptable stabilizers may include may include, but not limited to aminoethyl sulfonic acid, L-arginine, butylhydroxyanisol, polyvinylpyrrolidone, L-cysteine, cysteine hydrochloride, diethanolamine, diethylenetriaminepentaacetic acid, ferric chloride, inositol, D,L-methionine, or any combination thereof.

Examples of suitable pharmaceutically acceptable preservatives may include, but not limited to, chlorobutanol, benzalkonium chloride, methyl paraben, propyl paraben, benzoic acid, sodium benzoate, sorbic acid, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, benzyl alcohol, phenylmercury nitrate, phenylmercury acetate, thiomersal, merthiolate, chlorhexidine, phenylethyl alcohol, quaternary ammonium chloride, sodium benzoate, sodium propionate, or any combination thereof.

Examples of suitable pharmaceutically acceptable anti-oxidants may include, but not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, monothioglycerol, ascorbic acid, sodium ascorbate, erythorbic acid, potassium metabisulfite, sodium metabisulfite, propionic acid, sodium formaldehyde sulphoxylate, reduced glutathione, thiourea, cysteine, n-acetylcysteine, methionine, sodium sulfite, sodium bisulfate, alkyl gallate, including propyl gallate, vitamin E, or other tocopherol analogs, including tocopherol acetate or TPGS, or any combination thereof.

The stable aqueous parenteral solution of the present invention may comprise monothioglycerol in a concentration of between about 1 mg/mL and about 10 mg/mL, for example, about 2 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL or about 8 mg/mL.

Examples of suitable pharmaceutically acceptable surfactants may include, but not limited to, amphoteric, non-ionic, cationic or anionic molecules. Suitable surfactants may include, but not limited to, polysorbates 80 (e.g. tween 80 etc.), poloxamer (poloxamer 188), sodium lauryl sulfate, lauryl dimethyl amine oxide, docusate sodium, cetyl trimethyl ammonium bromide (CTAB), polyvinyl alcohol, polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, polyoxyl lauryl ether, Brij surfactants (polyoxyethylene vegetable-based fatty ethers derived from lauryl, cetyl, stearyl and oleyl alcohols), bile salts (such as sodium deoxycholate and sodium cholate), polyoxyl castor oil, nonylphenol ethoxylate, lecithin, polyoxyethylene surfactants, phospholipids such as dimyristoylphosphatidyl glycerol (DMPG), disteroylphosphatidylethanolamine (DSPE), 1,2-Distearoyl-phosphatidylethanolamine-methyl-polyethyleneglycol conjugate (DSPE-mPEG), monoalkanolamine condensates, polyoxyethylene fatty acid amides, quaternary ammonium salts, polyoxyethylene alkyl and alicyclic amines, polyoxyethylene, sorbitan monolaurate and stearate, Solutol® (ethylene oxide/12-hydroxy stearic acid), tyloxapol, or any combination thereof.

The stable aqueous parenteral solution of the present invention may comprise polysorbate 80 in a concentration of between about 1 mg/mL and about 100 mg/mL, for example, about 2 mg/mL, about 5 mg/mL, about 7 mg/mL, about 10 mg/mL, about 20 mg/mL, about 40 mg/mL, about 50 mg/mL, about 60 mg/mL or about 80 mg/mL.

Examples of suitable pharmaceutically acceptable buffering agents may include, but not limited to, acetate (e.g. sodium acetate etc.), citrate (e.g. citric acid/sodium citrate etc.), phosphate (e.g. monobasic sodium phosphate, dibasic sodium phosphate etc.), carbonate, or any combination thereof.

Examples of suitable pharmaceutically acceptable nucleation inhibitors may include, but not limited to, polyvinylpyrrolidone, crospovidone, hydroxypropylmethyl cellulose (HPMC), poloxamers, polysorbate, phospholipids such as dimyristoylphosphatidyl glycerol (DMPG), disteroylphosphatidylethanolamine (DSPE), 1,2-Distearoyl-phosphatidylethanolamine-methyl-polyethyleneglycol conjugate (DSPE-mPEG), or any combination thereof. In one embodiment, polyvinylpyrrolidone may be PVP K12, PVP K17, PVP K25, PVP K30, PVPK 40 or PVP K90.

Examples of suitable pharmaceutically acceptable pH adjusting agents may include, but not limited to, sodium hydroxide, hydrochloric acid, boric acid, citric acid, acetic acid, phosphoric acid, succinic acid, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, malic acid, potassium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine, or any combination thereof. The stable aqueous parenteral solution may comprise one or more pH adjusting agents in an amount to provide pH of the solution between about 8 and about 9, for example about 8.5.

Examples of suitable pharmaceutically acceptable isotonicity adjusting agents may include, but not limited to, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glucose, sucrose, dextrose, mannitol, glycerol, or any combination thereof.

The stable aqueous parenteral solution of the present invention may comprise sodium chloride in a concentration of between about 1 mg/mL and about 5 mg/mL, for example, about 2 mg/mL, about 3 mg/mL or about 4 mg/mL.

In another embodiment, the stable parenteral solution may comprise about 75 mg/mL of diclofenac, about 200 mg/mL of polyvinylpyrrolidone, about 20 mg/mL of polysorbate 80, about 5 mg/mL of monothioglycerol, one or more pH adjusting agents, for example, NaOH and/or HCl in a quantity sufficient to adjust pH of the solution about 8.5 and quantity sufficient water.

In another embodiment, the stable parenteral solution may comprise about 75 mg/mL of diclofenac, about 150 mg/mL of polyvinylpyrrolidone, about 20 mg/mL of polysorbate 80, about 5 mg/mL of monothioglycerol, one or more pH adjusting agents, for example, NaOH and/or HCl in a quantity sufficient to adjust pH of the solution about 8.5 and quantity sufficient water.

In another embodiment, the stable parenteral solution may comprise about 75 mg/mL of diclofenac, about 160 mg/mL of polyvinylpyrrolidone, about 20 mg/mL of polysorbate 80, about 5 mg/mL of monothioglycerol, one or more pH adjusting agents, for example, NaOH and/or HCl in a quantity sufficient to adjust pH of the solution about 8.5 and quantity sufficient water.

In another embodiment, the stable parenteral solution may comprise about 25 mg/mL of dicofenac, about 70 mg/mL of polyvinylpyrrolidone, about 7 mg/mL of polysorbate 80, about 5 mg/mL of monothioglycerol, about 3 mg/mL of sodium chloride, one or more pH adjusting agents, for example, NaOH and/or HCl in a quantity to adjust pH of the solution about 8.5 and quantity sufficient water.

In another embodiment, the stable parenteral solution may comprise about 37.5 mg/mL of dicofenac, about 80 mg/mL of polyvinylpyrrolidone, about 10 mg/mL of polysorbate 80, about 5 mg/mL of monothioglycerol, about 2 mg/mL of sodium chloride, one or more pH adjusting agents, for example, NaOH and/or HCl in a quantity to adjust pH of the solution about 8.5 and quantity sufficient water.

In another embodiment, the present invention provides a stable parenteral solution comprising diclofenac, polyvinylpyrrolidone, polysorbate 80 and water, wherein the solution is substantially free of co-solvent(s), for example, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethyl acetamide, benzyl alcohol, N-methyl pyrrolidone or glycerol formal, ethanol, transcutol, glycerol, cremophor (polyethoxylated castor oil), glycofurol, propylene glycol or polyethylene glycol. The term “substantially free of” as used herein, unless and otherwise specifically mentioned, means total amount of co-solvent(s) (organic and/or inorganic), if present in the solution, is less than 5% v/v of the solution, for example, less than 3% v/v, less than 1% v/v, or less than 0.5% v/v of the solution. The solution may be free of any co-solvent.

In another embodiment, the present invention provides a stable parenteral solution comprising diclofenac, polyvinlypyrrolidone and water, wherein diclofenac may be the only active ingredient present in the solution.

In another embodiment, the present invention provides a stable parenteral solution comprising diclofenac, polyvinlypyrrolidone and water, wherein the solution does not contain paracetamol (acetaminophen).

In another embodiment, the present invention provides a stable parenteral solution comprising diclofenac, polyvinlypyrrolidone and water, wherein the solution is not for any other route of administration except for the parenteral route of administration; for example, solution is not for the administration via ophthalmic route, otic route, topical route (application on skin) or oral route. The stable parenteral solution comprising diclofenac, polyvinlypyrrolidone and water is not an eye drop solution and/or ear drop solution.

In yet another embodiment, the present invention provides a method for the acute treatment of migraine attacks with or without aura in adults (18 years of age or older), the method comprising administering a solution comprising diclofenac via subcutaneous route.

In another embodiment, the present invention provides a stable parenteral solution comprising diclofenac, polyvinylpyrrolidone and water, wherein the solution is supplied/provided in a suitable packaging material, for example, in a glass vial, in a glass ampoule, in a pre-filled syringe, in a glass bottle, in a plastic bottle, in a plastic bag, etc. The pre-filled syringe contains various constituent parts, for example, a sterile clear USP Type-I siliconized glass syringe barrel (1 mL, cut flange with a gauge (29 size), hypodermic needle (½ inch) fitted with rigid needle shield and laminated bromobutyl plunger stopper for the barrel.

In another embodiment, the present invention provides a kit comprising an autoinjector which contains a pre-filled syringe (a pre-filled syringe assembled/placed in the autoinjector), wherein the pre-filled syringe contains a solution comprising diclofenac, polyvinylpyrrolidone and water.

In another embodiment, the present invention provides a kit comprising (a) a pre-filled syringe containing a solution comprising diclofenac, polyvinylpyrrolidone and water, and (b) an autoinjector device. The kit is suitable to administer the solution via subcutaneous route.

The autoinjector may be integrated with a needle stick protection feature and holds a pre-filled syringe containing a single dose, whereby the entire deliverable volume is expelled.

In another embodiment, the present invention provides a single-dose pre-filled syringe with an auto-injector, wherein the pre-filled syringe contains solution comprising 37.5 mg/mL diclofenac, polyvinylpyrrolidone and water, wherein the pre-filled syringe with an auto-injector is suitable to administer the effective amount of diclofenac dose via subcutaneous route for the acute treatment of migraine attacks with or without aura in adults 18 years of age or older.

In another embodiment, the present invention provides treatment of migraine attacks with or without aura in adults 18 years of age or older comprising administering to a human being in need thereof, diclofenac via subcutaneous route, wherein the onset of the action obtained after administering dicofenac via subcutaneous route is faster in comparison to the onset of action obtained after administering dicofenac via oral route, thereby providing quicker/faster onset of action.

In another embodiment, the present invention provides treatment of migraine attacks with or without aura in adults 18 years of age or older comprising administering to a human being in need thereof, diclofenac via subcutaneous route, wherein safety profile obtained after administering diclofenac via subcutaneous route may be better/improved in comparison to the safety profile obtained after administering diclofenac via oral route. The safety profile relates to, but not limited to, safety profile involving gastrointestinal (GI) adverse effects, for example, risk of GI ulceration, bleeding, and/or perforation.

In another embodiment, the present invention provides a diclofenac sodium injection, 37.5 mg/mL, in a single-dose pre-filled syringe with an auto-injector.

In another embodiment, the present invention provides a diclofenac sodium injection in a single-dose pre-filled syringe with an auto-injector, wherein the diclofenac is present in a therapeutically effective dose amount of 12.5 mg, 25 mg, 37.5 mg, 50 mg, 75 mg or 100 mg.

The stable aqueous parenteral solution does not contain any toxic and/or irritant ingredient, for example, any cyclodextrin derivative (HPBCD (hydroxypropyl-β-cyclodextrin), HPACD (hydroxypropyl-α-cyclodextrin), HPGCD (hydroxypropyl-γ-cyclodextrin), SBECD (sulfobutylether-β-cyclodextrin) etc.), transcutol, cremophor (polyethoxylated castor oil), glycofurol, propylene glycol and/or polyethylene glycol.

In another embodiment, the stable aqueous parenteral solution does not contain any local anesthetic, for example, lidocaine, prilocaine, tetracaine, bupivacaine, mepivacaine and/or xylocaine.

In another embodiment, the present invention provides a process for preparing a stable parenteral solution comprising diclofenac, polyvinylpyrrolidone, polysorbate 80, monothioglycerol and water. The process includes steps: (a) adding polyvinylpyrrolidone, polysorbate 80 and monothioglycerol into water to form a clear solution, (b) adding diclofenac into the solution prepared in step (a), and (c) adding pH adjusting agent, like NaOH/HCl to have a pH of the solution between about 8 and about 9. Additionally, the process may include adding an appropriate amount of NaCl at the step (a). The prepared solution may be subjected to a terminal sterilization process.

In another embodiment, the present invention provides a method for the treatment of pain and/or inflammation, the method comprising administering stable parenteral solution via parenteral route to a human being in need thereof. The parenteral route for the treatment of pain and/or inflammation is intravenous and/or intramuscular. The parenteral dose of dicofenac may range from about 12.5 mg to about 100 mg, for example, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg or 95 mg. The pain may be migraine pain.

In another embodiment, the present invention provides a method for the treatment of migraine attacks with or without aura to a human being in need thereof, the method comprising administering solution comprising diclofenac via subcutaneous route. The solution may further comprise polyvinylpyrrolidone and water. The solution may contain therapeutically effective amount of diclofenac to treat the migraine attacks. The individual in need of treatment of migraine attacks is an adult (18 years of age or older). The treatment of migraine attacks is acute and/or chronic. The treatment of migraine attacks with or without aura to a human being in need thereof comprising administering the solution of the present invention when administered via subcutaneous route may provide faster onset of the action in comparison to the onset of action obtained after administering diclofenac via oral route.

The solution comprising therapeutically effective amount of dicofenac to treat the migraine attacks of the invention may provide concentration of drug in plasma of at least 300 ng/mL, for example, at least 400 ng/mL, at least 500 ng/mL, at least 600 ng/mL, at least 700 ng/mL, at least 800 ng/mL, at least 900 ng/mL, at least 1000 ng/mL, at least 1500 ng/mL, at least 2000 ng/mL, at least 2500 ng/mL, at least 3000 ng/mL, at least 3500 ng/mL, at least 4000 ng/mL, at least 4500 ng/mL, at least 5000 ng/mL, at least 5500 ng/mL, at least 6000 ng/mL, at least 7000 ng/mL, at least 7500 ng/mL, at least 8000 ng/mL, at least 8500 ng/mL, at least 9000 ng/mL, at least 9500 ng/mL or at least 10,000 ng/mL, in less than 15 minutes, when the solution is administered via subcutaneous route.

The solution comprising therapeutically effective amount of diclofenac to treat the migraine attacks of the invention may provide value of T_(max) less than 60 minutes, for example, less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, less than 15 minutes or less than 10 minutes, less than 9 minutes, less than 8 minutes, less than 7 minutes, less than 6 minutes, less than 5 minutes, less than 4 minutes, less than 3 minutes, less than 2 minutes or less than 1 minute, when the solution is administered via subcutaneous route.

The solution comprising diclofenac to treat the migraine attacks of the invention may provide value of C_(max) more than 1000 ng/mL, for example, more than 1100 ng/mL, more than 1200 ng/mL, more than 1300 ng/mL, more than 1400 ng/mL, more than 1500 ng/mL, more than 1600 ng/mL, more than 1700 ng/mL, more than 1800 ng/mL, more than 1900 ng/mL, more than 2000 ng/mL, more than 2100 ng/mL, more than 2200 ng/mL, more than 2300 ng/mL, more than 2400 ng/mL, more than 2500 ng/mL, more than 2600 ng/mL, more than 2700 ng/mL, more than 2800 ng/mL, more than 2900 ng/mL, more than 3000 ng/mL, more than 3500 ng/mL, more than 4000 ng/mL, more than 4500 ng/mL, more than 5000 ng/mL, more than 5500 ng/mL, more than 6000 ng/mL, more than 6500 ng/mL, more than 7000 ng/mL, more than 7500 ng/mL, more than 8000 ng/mL, more than 8500 ng/mL, more than 9000 ng/mL, more than 9500 ng/mL, more than 10,000 ng/mL, more than 10,500 ng/mL, more than 11,000 ng/mL, more than 11,500 ng/mL, more than 12,000 ng/mL, more than 12,500 ng/mL, more than 13,000 ng/mL, more than 13,500 ng/mL, more than 14,000 ng/mL, more than 14,500 ng/mL or more than 15,000 ng/mL, when the solution is administered via subcutaneous route to a human at a diclofenac dose of 12.5 mg, 25 mg, 37.5 mg, 50 mg, 75 mg or 100 mg.

The solution comprising diclofenac to treat the migraine attacks of the invention may provide value of AUC_(last) more than 500 ng*h/mL, more than 600 ng*h/mL, more than 700 ng*h/mL, more than 800 ng*h/mL, more than 900 ng*h/mL, more than 1000 ng*h/mL, more than 1100 ng*h/mL, more than 1200 ng*h/mL, more than 1300 ng*h/mL, more than 1400 ng*h/mL, more than 1500 ng*h/mL, more than 1600 ng*h/mL, more than 1700 ng*h/mL, more than 1800 ng*h/mL, more than 1900 ng*h/mL, more than 2000 ng*h/mL, more than 2100 ng*h/mL, more than 2200 ng*h/mL, more than 2300 ng*h/mL, more than 2400 ng*h/mL, more than 2500 ng*h/mL, more than 2600 ng*h/mL, more than 2700 ng*h/mL, more than 2800 ng*h/mL, more than 2900 ng*h/mL, more than 3000 ng*h/mL, more than 3500 ng*h/mL, more than 4000 ng*h/mL, more than 4500 ng*h/mL, more than 5000 ng*h/mL, more than 5500 ng*h/mL, more than 6000 ng*h/mL, more than 6500 ng*h/mL, more than 7000 ng*h/mL, more than 7500 ng*h/mL, more than 10,000 ng*h/mL, more than 12,500 ng*h/mL, more than 15,000 ng*h/mL, more than 17,500 ng*h/mL, more than 20,000 ng*h/mL, more than 22,500 ng*h/mL or more than 25,000 ng*h/mL, when the solution is administered via subcutaneous route to a human at a diclofenac dose of 12.5 mg, 25 mg, 37.5 mg, 50 mg, 75 mg or 100 mg.

In another embodiment, the physical and chemical stability of the parenteral solution of the present invention was studied at 25° C. temperature and 60% relative humidity (% RH) as well as at 40° C. temperature and 75% RH.

ABBREVIATIONS

-   ND: Not Detected. -   NMT: Not More Than. -   BQL: Below Quantitation Limit. -   BDL: Below Detection Limit. -   NLT: Not Less Than. -   q.s.: Quantity Sufficient.

The present invention is illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention.

Example 1

TABLE 1 Sr. no. Ingredients Amount in mg 1 Diclofenac sodium 1500 2 Polyvinylpyrrolidone K12 4000 3 Polysorbate 80  400 4 Sodium hydroxide q.s. to pH 8.5 5 Monothioglycerol  100 6 Water for Injection q.s. to 20 mL

Process:

All the ingredients were used in an amount mentioned in Table 1, for preparing diclofenac injection solution, batch size 20 mL.

Polyvinylpyrrolidone K12, polysorbate 80 and monothioglycerol were added into 16 mL of water for injection, stirred and dissolved completely at controlled room temperature. Diclofenac sodium was added to the above prepared solution with moderate stirring at controlled room temperature. Then pH of the solution was adjusted to 8.5 using 5% w/v NaOH and/or 5% w/v HCl and the volume was made up to 20 mL using water for injection. The solution was filtered through a 0.22p filter and filled into an amber colored glass vial.

Example 2

TABLE 2 Amount in mg Solution Solution 2A Solution 2B Diclofenac sodium 1500 1500  Polyvinylpyrrolidone K12 3000 — Polysorbate 80  400 400 Sodium hydroxide q.s. to pH 8.5 q.s. to pH 8.5 Monothioglycerol  100 100 Water for Injection q.s. to 20 mL q.s. to 20 mL

Process:

The process for preparing example 2 is the same as the process for preparing example 1, with the exception that solution 2A contains 150 mg/mL polyvinylpyrrolidone K12 and solution 2B does not contain polyvinylpyrrolidone K12.

The solution 2A and solution 2B were tested for their physical stability and chemical stability, and the results are reported in the Table 2A below.

TABLE 2A Chemical stability Physical stability (Impurity A) Storage Initial 1 day/ 1 day/ Initial 1 day/ conditions 25° C. 2-8° C. 80° C. Solution 2A Clear solution Clear Clear ND 0.13% solution solution Solution 2B Unstable. — — ND 0.35% Crystallization of diclofenac occurs within 2 minutes of preparing the solution.

It is evident from a comparison of the stability data for solution 2A and solution 2B, provided at the above Table 2A, that polyvinylpyrrolidone provides physical as well as chemical stability to diclofenac sodium in the liquid injection solution.

Example 3

TABLE 3 Sr. no. Ingredients mg/mL 1 Diclofenac sodium 75 2 Polyvinylpyrrolidone K12 160  3 Polysorbate 80 20 4 Sodium hydroxide q.s. to pH 8.5 5 Hydrochloric acid q.s. to pH 8.5 6 Monothioglycerol  5 7 Water for Injection q.s. to 1 mL

Process:

All the ingredients were used in a concentration as mentioned in Table 3, for preparing diclofenac injection solution having a batch size 500 mL.

In measured quantity of water for injection, nitrogen was sparged until dissolved oxygen was at a level up to 2 ppm. Polyvinylpyrrolidone K12 was added into 350 mL (70% amount of total batch size) of nitrogen sparged water for injection and dissolved by stirring at room temperature. Monothioglycerol was added into the above prepared solution. Polysorbate 80 was added to the above prepared solution and dissolved by stirring. Diclofenac sodium was added to the above prepared solution and dissolved by stirring at room temperature. Then, pH of the solution was adjusted to 8.5 using 5% w/v NaOH and/or 5% w/v HCl, and the volume was made up to 500 mL using nitrogen sparged water for injection. The solution was filtered through a 0.2μ sterile filter and filled into a clear glass ampoule under pre- and post-nitrogen flushing.

The solution of Example 3 was tested for certain parameters at various storage conditions, viz., storage at 25° C. temperature and 60% RH as well as at 40° C. temperature and 75% RH and for various storage times, viz., 3 months (3M), 6 months (6M), 12 months (12M) and 24 months (24M). The results are reported in the Table 3A below.

TABLE 3A Storage conditions Parameters Initial 3 M 6 M 12 M 24 M 25° C./ Description Clear Clear Clear Clear Clear 60% RH solution solution solution solution solution Assay (%) 101.900 102.300 102.700 101.700 101.900 Impurity A ND ND BQL BQL BQL pH 8.720 8.450 8.480 8.360 8.590 Absorbance 0.057 0.140 0.180 0.271 0.231 % Transmittance 100.000% 99.900% 99.700% 99.000% 99.300% Viscosity (cP) 6.310 — 5.910 — — Osmolality 485 445 438 434 434 (mOsm) 40° C./ Description Clear Clear Clear — — 75% RH solution solution solution Assay (%) 101.900 103.000 102.700 — — Impurity A ND 0.02% 0.11% — — pH 8.720 8.370 8.450 — — Absorbance 0.057 0.417 0.502 — — % Transmittance 100.000% 98.100% 99.700% — — Viscosity (cP) 6.310 — 5.930 — — Osmolality 485 450 446 — — (mOsm)

Measurement of absorbance and transmittance was done by UV spectrophotometer.

Measurement of viscosity was done by brookield viscometer, model DV2T.

Measurement of osmolality (mOsm) was done by osmometer.

Measurement of assay (%) was done by HPLC (high performance liquid chromatography).

The solution of Example 3 was diluted using appropriate quantities of saline solution (0.9% sodium chloride) to achieve diluted solutions comprising diclofenac in a concentration of 0.75 mg/mL, 0.30 mg/mL, and 0.15 mg/mL. All three diluted solutions were tested for certain parameters (i) at initial time point (To), (ii) after 24 hours storage at controlled room temperature (25° C.±2° C.), and (iii) after 24 hours storage at 2-8° C. temperature. The results are reported in the Table 3B below.

TABLE 3B Diclofenac Total Na conc. pH Assay (%) Impurities (mg/mL) Temp. Description T₀ 24 hrs T₀ 24 hrs T₀ 24 hrs 0.75 CRT Clear 7.20 6.65 100.40 100.60 BQL BQL 0.30 CRT Clear 6.95 6.45 96.90 100.10 0.06 0.02 0.15 CRT Clear 6.63 6.25 99.00 98.80 ND BQL 0.75 2-8° C. Clear 7.20 6.50 100.50 101.10 ND BQL 0.30 2-8° C. Clear 6.95 6.28 96.60 98.60 BQL BQL 0.15 2-8° C. Clear 6.63 6.08 98.90 98.80 BQL BQL

Example 4

TABLE 4 Sr. no. Ingredients mg/mL 1 Diclofenac sodium 25 2 Polyvinylpyrrolidone K12 70 3 Polysorbate 80  7 4 Sodium chloride  3 5 Sodium hydroxide q.s. to pH 8.5 6 Hydrochloric acid q.s. to pH 8.5 7 Monothioglycerol  5 8 Water for Injection q.s. to 1 mL

Process:

All the ingredients were used in a concentration as mentioned in Table 4, for preparing diclofenac injection solution having a batch size 1400 mL.

The process for preparing Example 4 is same as the process for preparing Example 3, with the exception that Example 4 contains an additional step of addition of sodium chloride and dissolved by stirring, after addition of polysorbate 80 and before the addition of diclofenac sodium.

The solution of Example 4 was tested for certain parameters at various storage conditions, viz., storage at 25° C. temperature and 60% RH as well as at 40° C. temperature and 75% RH and for various storage times, viz., 3 months (3M), 6 months (6M), 12 months (12M) and 18 months (18M). The results are reported in the Table 4A below.

TABLE 4A Storage conditions Parameters Initial 3 M 6 M 12 M 18 M 25° C./ Description Clear Clear Clear Clear Clear 60% RH solution solution solution solution solution Assay (%) 102.900 103.100 102.400 99.900 102.700 Impurity A ND BQL BQL BQL 0.03% pH 8.770 8.420 8.560 8.490 8.590 Absorbance 0.034 0.067 0.099 0.156 0.178 % Transmittance 99.500% 98.800% 99.000% 98.900% 98.600% Viscosity (cp) 1.79 — — — — Osmolality 340 329 335 306 311 (mOsm) 40° C./ Description Clear Clear Clear — — 75% RH solution solution solution Assay (%) 102.900 101.800 100.700 — — Impurity A ND 0.060% 0.280% — — pH 8.770 8.460 8.580 — — Absorbance 0.034 0.215 0.234 — — % Transmittance 99.500% 98.900% 98.800% — — Viscosity (cP) 1.790 — — — — Osmolality 340 315 326 — — (mOsm)

Example 5

TABLE 5 Sr. no. Ingredients mg/mL 1 Diclofenac sodium 37.5 2 Polyvinylpyrrolidone K12 80 3 Polysorbate 80 10 4 Sodium chloride 2 5 Sodium hydroxide q.s. to pH 8.5 6 Hydrochloric acid q.s. to pH 8.5 7 Monothioglycerol 5 8 Water for Injection q.s. to 1 mL

Process:

All the ingredients were used in a concentration as mentioned in Table 5, for preparing diclofenac injection solution having a batch size 500 mL.

The process for preparing Example 5 is same as the process for preparing Example 4.

The solution of Example 5 was tested for certain parameters parameters at various storage conditions, viz., storage at 25° C. temperature and 60% RH as well as at 40° C. temperature and 75% RH and for various storage times, viz., 3 months (3M), 6 months (6M), 12 months (12M) and 18 months (18M). The results are reported in the Table 5A below.

TABLE 5A Storage conditions Parameters Initial 3 M 6 M 12 M 18 M 25° C./ Description Clear Clear Clear Clear Clear 60% RH solution solution solution solution solution Assay (%) 103.200 103.900 102.6% 104.2% 102.7% Impurity A BQL 0.010% 0.020% 0.030% 0.020% pH 8.290 8.120 8.150 8.280 8.310 Absorbance 0.047 0.139 0.156 0.282 0.371 % Transmittance 99.700% 99.500% 99.400% 99.200% 97.800% Viscosity (cP) 2.080 — — — — Osmolality 334 322 326 322 315 (mOsm) 40° C./ Description Clear Clear Clear Clear — 75% RH solution solution solution solution Assay (%) 103.200 101.500 103.100 101.000 — Impurity A BQL 0.090% 0.310% 0.650% — pH 8.290 8.170 8.220 8.290 — Absorbance 0.047 0.333 0.380 0.502 — % Transmittance 99.700% 99.700% 98.700% 98.000% — Viscosity (cP) 2.080 — — — — Osmolality 334 324 335 326 — (mOsm)

Example 6 Preparation of Prefilled Syringe Assembled/Placed in the Autoinjector

The diclofenac solution for Example 6 is prepared in the same way as prepared in Example 5, except, filling of the solution into a clear glass ampoule, the solution has been filled into a glass syringe followed by assembling/placing the pre-filled syringe in an auto-injector.

The solution of Example 6 was tested for certain parameters at various storage conditions, viz., storage at 25° C. temperature and 60% RH as well as at 40° C. temperature and 75% RH and for various storage times, viz., 3 months (3M) and 6 months (6M). The results are reported in the Table 6

TABLE 6 Storage conditions Parameters Initial 3 M 6 M 25° C./ Description Clear Clear Clear 60% RH solution solution solution Assay (%) 101.500% 101.000% 101.400% Impurity A ND BDL BDL pH 8.4 8.3 8.3 Absorbance 0.030 0.110 0.110 % Transmittance 99.400% 99.000% 100.000% Osmolality (mOsm) 322 317 312 40° C./ Description Clear Clear Clear 75% RH solution solution solution Assay (%) 101.500% 100.700% 101.000% Impurity A ND 0.140% 0.350% pH 8.4 8.3 8.3 Absorbance 0.030 0.300 0.410 % Transmittance 99.400% 98.900% 99.700% Osmolality (mOsm) 322 316 315

It is evident from a comparison of the stability data for Example 3, Example 4, Example 5 and Example 6, provided in the above Table 3A & 3B, Table 4A, Table 5A and Table 6, respectively that diclofenac solution of the present invention remains physically and chemically stable initially as well as upon storage at various storage conditions and primary packagings.

Example 7 Pharmacokinetic Study in Rats

Test product prepared in Example 5 was used for the study.

Animal model Wistar rat Route of administration IV (group 1), IM (group 2), SC (group 3) Fasting/Non-fasting Non fasting, free access of feed and water ad libitum Dose 3.9 mg/kg (37.5 mg human equivalent dose considering 60 kg human weight)

Pharmacokinetic Parameters:

Parameter IM SC C_(max) (ng/mL) 5985.1 ± 1300.9 6419.1 ± 1093.6 AUC_(last) (ng * h/mL) 4780.6 ± 787.0  5083.0 ± 866.5  AUC_(int) (ng * h/mL) 4876.3 ± 818.0  5190.0 ± 926.3  T_(max) (minutes) 15 10 T_(1/2) (hours) 1.9 ± 0.5 2.0 ± 0.5 Bioavailability (%) −73 (Comparative −77.5 (Comparative to IV) to IV)

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. 

The invention claimed is:
 1. A parenteral solution comprising diclofenac, polyvinylpyrrolidone, one or more pH adjusting agents, and water, wherein the solution has a pH of between about 7 and about
 10. 2. The parenteral solution according to claim 1, wherein the solution further comprises polysorbate 80 and sodium chloride.
 3. The parenteral solution according to claim 1, wherein the diclofenac is present as diclofenac sodium.
 4. The parenteral solution according to claim 3, wherein the diclofenac sodium is present in a concentration of between about 37.5 mg/mL and about 75 mg/mL.
 5. The parenteral solution according to claim 1, wherein the polyvinylpyrrolidone is present in a concentration of between about 50 mg/mL and about 200 mg/mL.
 6. The parenteral solution according to claim 2, wherein the polysorbate 80 is present in a concentration of between about 5 mg/mL and about 20 mg/mL.
 7. The parenteral solution according to claim 1, wherein the solution has a viscosity of between about 1.5 cP and about 7.5 cP.
 8. The parenteral solution according to claim 1, wherein the solution remains clear after storage for 12 months at controlled room temperature.
 9. The parenteral solution according to claim 1, wherein the solution does not contain impurity A more than 0.5% after storage for 12 months at controlled room temperature.
 10. A method for the treatment of pain, the method comprising administering to a human being in need thereof, a solution, via parenteral route, comprising diclofenac, polyvinylpyrrolidone, polysorbate 80, sodium chloride, one or more pH adjusting agents, water, optionally one or more preservatives, optionally one or more antioxidants, and optionally one or more buffering agents, wherein the solution has a pH of between about 7 and about
 10. 11. The method according to claim 10, wherein the solution is provided in a pre-filled syringe.
 12. The method according to claim 11, wherein the pre-filled syringe is assembled/placed in an autoinjector.
 13. A method for treatment of migraine, the method comprising administering to a human being in need thereof, a solution, via parenteral route, comprising diclofenac, polyvinylpyrrolidone, polysorbate 80, sodium chloride, one or more pH adjusting agents, water, optionally one or more preservatives, optionally one or more antioxidants, and optionally one or more buffering agents, wherein the solution has a pH of between about 7 and about
 10. 14. The method according to claim 13, wherein the method is for the acute treatment of migraine attacks.
 15. The method according to claim 13, wherein the parenteral route is a subcutaneous route.
 16. The method according to claim 13, wherein the method comprises administering the solution of diclofenac via subcutaneous route, and wherein the diclofenac is present from about 12.5 mg to about 100 mg. 